Gels correspond to an intermediate state of matter containing both solid and liquid components. The solid elements form a three-dimensional structure or matrix, organized as a network of mutually interconnected molecules. This network immobilizes the elements present in liquid form.
In hydrogels, the liquid medium is aqueous, whereas in organogels the liquid medium is an organic solvent.
Gels may also be classified based on the nature of the bonds that link together the molecules of the solid elements. Chemical gels arise when strong covalent bonds hold the network together, and physical gels when hydrogen or Van der Waals bonds or electrostatic interactions maintain the gel network.
In the case of heat-sensitive gels, the temperature at which the change of state is observed is known as the transition temperature. In the particular case of systems showing hysteretic behaviour, the gel/liquid transition temperature is different from the liquid/gel transition temperature.
Gels may be used in the pharmaceutical industry for their retention capacity with respect to bioactive molecules, especially in the context of a transcutaneous administration of active substances. Also, implantable gels have already been used for in situ delivery of active principle. However, this type of use necessitates the surgical implantation of a preformed gel, operation that remains both expensive and a limitation for the patient.
Organogels are systems composed of an organic solvent with a three-dimensional network of self-assembled compounds. The compounds, commonly called “organogelators” or “organogelling substances”, are essentially low molecular weight molecules. The physical association between organogelator molecules forms a solid network which is able to immobilize the organic solvent. Research on these matrices is recent and has grown rapidly with the continuous development of organogelator molecules.
Unfortunately, there are only few studies describing the use of organogels in drug delivery. This can be partly explained by the fact that most matrices under investigation may be potentially toxic. In the pharmaceutical field, organogels have been mainly studied for the transdermal delivery of drugs (Upadhyay K K et al, 2007 and Lim P F C et al., 2006).
WO99/56725 describes a composition containing phospholipids as organogelators, dedicated to be injected into a body, and that forms spontaneously a gel when encountering physiological fluids. Such a composition can be easily used as a vector for active principle. Before injection, it is liquid. After injection, it gels by absorbing the surrounding aqueous phase.
Other work also reports organogels that can be injected and serve as active principle carriers, based on alanine methyl ester, that are modified with a stearoyl chain (C18): S-AlaOCH3 (WO03/075885). This type of organogelator has the advantages of a straightforward synthesis and bio compatibility. This organogel serves as a support for the sustained release of active principles by diffusion and/or erosion and/or gradual biodegradation of the organogel in the body. In this case, organogels are formed by diffusion of an hydrophilic solvent added to the composition, or by cooling of the site of injection during several minutes.
The present invention is based on the surprising discovery by the present inventors that Tyrosine derivatives such as N-Behenoyl L-tyrosine methyl ester (B-TyrOCH3) or N-Stearoyl L-tyrosine methyl ester (S-TyrOCH3) are able to form organogels with improved physical properties, for example a better gel hardness, especially compared to those obtained from alanine derivatives. This property may allow to decrease the concentration of organogelator in the organogel, and hence to increase the concentration of active principle in the organogel. It may also permit to obtain implants that resist in vivo longer than Alanine-based organogels, hence releasing the drug for a longer time than the S-AlaOCH3 formulations.
The organogel according to the present invention, when obtained with a low concentration of organogelling substance, is already in gel state before injection. Contrary to compositions of the prior art, there is no need of cooling, diffusing nor absorbing fluids to form the gel in situ in a body.
In addition, the composition according to the present invention has the advantage of being extremely inexpensive, both in terms of manufacture as is described later, and in terms of packaging and administration.